title: Isomeric trimethylene and ethylene pendant-armed cross-bridged tetraazamacrocycles and in vitro/in vivo comparisions of their copper(II) complexes.
abstract: Ethylene cross-bridged tetraamine macrocycles are useful chelators in coordination, catalytic, medicinal, and radiopharmaceutical chemistry. Springborg and co-workers developed trimethylene cross-bridged analogues, although their pendant-armed derivatives received little attention. We report here the synthesis of a bis-carboxymethyl pendant-armed cyclen with a trimethylene cross-bridge (C3B-DO2A) and its isomeric ethylene-cross-bridged homocyclen ligand (CB-TR2A) as well as their copper(II) complexes. The in vitro and in vivo properties of these complexes are compared with respect to their potential application as (64)Cu-radiopharmaceuticals in positron emission tomography (PET imaging). The inertness of Cu-C3B-DO2A to decomplexation is remarkable, exceeding that of Cu-CB-TE2A. Electrochemical reduction of Cu-CB-TR2A is quasi-reversible, whereas that of Cu-C3B-DO2A is irreversible. The reaction conditions for preparing (64)Cu-C3B-DO2A (microwaving at high temperature) are relatively harsh compared to (64)Cu-CB-TR2A (basic ethanol). The in vivo behavior of the (64)Cu complexes was evaluated in normal rats. Rapid and continual clearance of (64)Cu-CB-TR2A through the blood, liver, and kidneys suggests relatively good in vivo stability, albeit inferior to (64)Cu-CB-TE2A. Although (64)Cu-C3B-DO2A clears continually, the initial uptake is high and only about half is excreted within 22 h, suggesting poor stability and transchelation of (64)Cu to proteins in the blood and/or liver. These data suggest that in vitro inertness of a chelator complex may not always be a good indicator of in vivo stability.
authors.affiliation: Department of Chemistry, University of New Hampshire, Durham, New Hampshire 03824, USA.
authors.forename: Antoinette Y
authors.initials: AY
authors.lastname: Odendaal
authors.forename: Ashley L
authors.initials: AL
authors.lastname: Fiamengo
authors.forename: Riccardo
authors.initials: R
authors.lastname: Ferdani
authors.forename: Thaddeus J
authors.initials: TJ
authors.lastname: Wadas
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Hill
authors.forename: Yijie
authors.initials: Y
authors.lastname: Peng
authors.forename: Katie J
authors.initials: KJ
authors.lastname: Heroux
authors.forename: James A
authors.initials: JA
authors.lastname: Golen
authors.forename: Arnold L
authors.initials: AL
authors.lastname: Rheingold
authors.forename: Carolyn J
authors.initials: CJ
authors.lastname: Anderson
authors.forename: Gary R
authors.initials: GR
authors.lastname: Weisman
authors.forename: Edward H
authors.initials: EH
authors.lastname: Wong
mesh_terms: D001372:Aza Compounds / Q000737:chemistry*; D003300:Copper / Q000737:chemistry*; D018360:Crystallography, X-Ray; D003521:Cyclopropanes / Q000737:chemistry*; D005030:Ethylenes / Q000737:chemistry*; D047028:Macrocyclic Compounds / Q000737:chemistry; D008958:Models, Molecular; D015394:Molecular Structure; D009942:Organometallic Compounds / Q000138:chemical synthesis / Q000737:chemistry*; D013237:Stereoisomerism
chemical_list: D001372:Aza Compounds; D003521:Cyclopropanes; D005030:Ethylenes; D047028:Macrocyclic Compounds; D009942:Organometallic Compounds; D003300:Copper; C036216:ethylene; C030797:cyclopropane